It is believed that during mechanical ventilation (MV), over-distension of lung units and/or shear forces generated during repetitive opening and closing of collapsed airways and atelectatic alveolar regions can exacerbate and may even trigger lung injury leading to inflammation and potentially to multiple-system organ failure. Recently, we have reported that during MV, variability added to tidal volume (Vt) and frequency on a cycle by cycle basis, called variable ventilation(VV), improves both lung mechanics and oxygenation in a rodent model of acute lung injury. Furthermore, healthy guinea pigs that underwent VV exhibited increased surfactant content and reduced plasma proteins and cytokine levels within the alveolar space compared to those that received conventional MV. This suggests that not only did VV induce endogenous surfactant release, but also served to reduce ventilator induced lung injury and inflammation in this animal model. Based on these observations, we formulate the following two primary hypotheses of this proposal: 1) Compared to the currently accepted low Vt ventilation strategy, VV provides an increased protection of the lung against the development of VILI by improving alveolar recruitment, which decreases cellular damage, inflammation and cytokine release; and 2) The amount of variability in VV can be "tuned" such that the stretch patterns applied to alveolar epithelium serve to stimulate surfactant production and maximize surfactant release while minimizing the risks of damaging the epithelium and generating inflammation. To test these hypotheses, we set up three specific aims: 1) To determine lung function characterized by mechanics, gas exchange and surfactant composition as a function of the variability included in VV and the positive end-expiratory pressure in normal guinea pigs. Rationale: This aim will test whether gradually adding variability to MV improves the physiological and biological response of the lung during long-term ventilation and whether there exists an optimal level of variability in relation to the pressure-volume curve of the lung at which mechanics, gas exchange, and surfactant composition are least compromised. Mechanics, blood gases, surfactant composition will be measured and the amount and heterogeneity of lung injury will be assessed from histopathological evaluation of the lung structure as a function of variability. 2) To determine whether a similar optimization of mechanics, gas exchange and surfactant composition is possible in a rodent model of endotoxin-induced acute lung injury. Rationale: This aim will allow us to test whether VV is also effective in minimizing the risk of exacerbation of pre-existing lung injury. 3) To determine whether the variable stretch pattern imparted by VV on the alveolar epithelium stimulates the production and secretion of phospholipids (PL) and surfactant proteins (SP). Rationale: By measuring PL and SP levels together with the appropriate RNA levels, we will determine whether the mechanical stretch patterns in VV stimulate gene expression or not. Significance: If VV is able to minimize the deleterious effects of mechanical forces on the alveolar compartment while simultaneously stimulate upregulation of surfactant, then VV will, in essence, provide a simple mechanical ventilation strategy capable of inducing therapeutic "endogenous surfactant replacement."